Quality control is a major concern to manufacturers of sterile parenteral products. The exclusion of particulate and microbial contamination during all phases of production and storage of sterile parenterals is of paramount importance if product quality is to be guaranteed. An added packaging requirement is the capability of the container in preventing the entry of contamination during storage. According to the USP Product Defect Reporting System, numerous incidents of contamination in parenteral products have been traced to faulty seals.
Sterile products are available in many dosage forms, and are packaged principally in single or multiple dose containers. Multiple dose containers use a rubber stopper as a seal so that the product is resealed following withdrawal of doses. In order to further assure sterility, products packaged in multiple dose containers generally include a preservative to guard against accidental contamination. Single dose ampules or stoppered vials generally do not contain a preservative. Therefore, a specific requirement for glass ampules is that they must be completely sealed to avoid the entry of outside contamination.
Sealing an ampule after it is filled with solution consists of heating the neck of the ampule until soft, then rotating the ampule and pulling the tip simultaneously for pull seals. For tip sealing, the open end is flamed and sealed while the ampule is continually rotated. The simplicity of the procedure, however, is deceptive and imperfections in the seal can arise in several ways. The duration of heating may be insufficient to cause complete closure, or it may be excessive, thereby causing fragile bubbles to form which may break during or after heating. The ampule may become too hot during sealing and fracture when cooled, or the speed of rotation may be slow or erratic, causing uneven heating of the ampule and subsequent cracking during cooling. The possibility of contamination of the product through minute cracks or holes in the wall of an ampule makes the detection of such imperfections imperative if sterility and stability are to be assured.
The most popular test for this purpose is called the "leaker test". Its merits and shortcomings have been discussed by several authors (D. E. McVean, P. A. Tuerck, G. L. Christenson, and J. T. Carstensen, "Inadequacies in Leakage Test Procedures for Flame-sealed Ampules", J. Pharm. Sci., 61, (10) 1609-1611 (1972) and W. J. Artz, W. T. Gloor, Jr., and D. R. Reese, "Study of Various Methods for Detecting Leaks in Hermetically Sealed Ampules", J. Pharm. Sci., 50(3) 258-262 (1961)). At least three variations on this procedure exist (D.P.S.C. Standards for the Manufacture and Packaging of Drugs, Pharmaceuticals, and Biological Products, Defense Personnel Support Center, Philadelphia, Pa., September 1968, Appendix II, p. 52). If they are terminally sterilized, the hot ampules are immediately submerged in a room temperature dye bath, rinsed, dried, and visually inspected for color against a white background. A partial vacuum is created in the ampules as the hot liquid contracts, which draws dye solution inside through any flaws in the seal. If the product, on the other hand, is aseptically prepared (cold sterilization), the sealed ampules are inverted and floated in an indicator dye solution in a vessel which can be evacuated or pressurized. Vacuum or pressure is applied for about one minute, then released. The ampules are rinsed, dried, and inspected as in the hot method. In any of these methods, a change of color in the ampule's contents indicates a "leaker" which is subsequently rejected from the lot.
Two major problems are associated with the leaker test. First, the colors of most commonly used indicator dyes are dependent on the pH, and second, visual detection of color depends on the intensity of the color.
The first problem can be overcome if an indicating dye is carefully chosen for each product which will definitely produce color in that product. The second problem, though, is much more difficult to solve. The amount of dye which will enter an ampule is unpredictable unless the size of the aperture constituting the imperfection in the seal is known. Many leakers may go undetected by an inspector because the concentration of dye in the ampule is insufficient to produce a color of discernible intensity.
Choosing an appropriate dye for each product to be tested is bothersome, and it is risky to assume that a negative result from a subjective test such as color detection by visual inspection conclusively indicates an intact seal. Therefore, it seems appropriate to develop a more universal, more sensitive, and more objective procedure for detecting faulty seals in ampules (leakers).